Friday, October 2, 2020

How are COVID-19 vaccine manufacturers aiming to encourage trust in the FDA’s approval process?

By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

In recent weeks, a number of articles have reported great concern around the politicization of the approval process for future COVID-19 vaccines. Public trust in public health agencies is arguably at an all-time low. After several missteps, the FDA has been working publicly to shore up public confidence in an approved vaccine once it comes out. But pharmaceutical companies themselves are now also engaging the public themselves in an attempt to build trust in their products. This is an unusual step for, of course, unusual times. What are vaccine developers doing, how should policymakers think about these efforts, and how can we encourage these lines of communication in the future?

What steps have vaccine manufacturers been taking to communicate with the public? 

Nothing has been usual about the COVID-19 vaccine development process so far, including the unprecedented steps taken by vaccine developers to communicate with the public. We think at least three facets of this strategy are worth noting.

First, vaccine developers have taken unprecedented public positions on the FDA approval process. On September 8, the CEOs of nine leading firms in the COVID-19 vaccine race—AstraZeneca, BioNTech, GlaxoSmithKline, Johnson & Johnson, Merck, Moderna, Novavax, Pfizer, and Sanofi—signed a pledge to “stand with science” in developing their vaccines. The stated goal is to “help ensure public confidence” in the approval process. The statement praises the FDA’s guidance for COVID-19 vaccines as based on “scientific and medical principles,” including the requirement for large, randomized, double-blind clinical trials across diverse populations. (The pledge came before the FDA announced that it planned to issue even tougher standards, although it now appears as if the White House has blocked the public release of those standards.) The most concrete pledge is to “[o]nly submit for approval or emergency use authorization after demonstrating safety and efficacy through a Phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA” (emphasis added). This might do something to quell the alarm that followed FDA Commissioner Stephen Hahn’s statement that the agency might authorize a vaccine before Phase 3 trials are complete. The firms have not, however, necessarily bound themselves to the specific 50% efficacy requirement from the June 30 guidance

Second, although the “stand with science” pledge did not make any promises about disclosure of clinical trial design or data, some firms have independently released their trial protocols. Pfizer and Moderna published theirs on September 17, AstraZeneca followed suit on September 19, and Johnson & Johnson released theirs a few days later. As former FDA Commissioner Dr. Robert Califf has noted, current HHS regulations (effective January 2017) require this information to be disclosed eventually: the study protocol and statistical analysis plan must be disclosed on along with clinical trial results, generally within 1 year after completing the trial. But enforcement of these requirements is spotty, and releasing trial protocols while studies are ongoing is unusual and demonstrates that the CEOs are taking public communication and trust seriously. Of course, the trial protocols are not designed for lay audiences—each one contains over 100 pages of technical details—but publishing them may help shore up expert confidence. Experts such as Dr. Eric Topol have been combing through the protocols to summarize and compare them in ways accessible to those without a background in study design.

Third, vaccine developers have taken unusual steps to communicate with Americans more directly. For example, Pfizer CEO Albert Bourla has recently gone on shows like the Today show and Face the Nation, and Moderna CEO Stephen Hoge appeared on CBS Evening News. Both have provided information about when we will realistically know whether their vaccines work—Bourla expects results by the end of October, Hoge thinks November or December—and have admirably (and correctly) noted that this does not mean that distribution would start then. Both have also tried to restore public confidence in the process, including by promoting their “stand with science” pledge and protocol disclosure. Hoge acknowledged that “one of the biggest challenges we have” is “building confidence in the vaccine” while “mak[ing] sure we’re making the right scientific choices and we’re presenting honestly the uncertainties around those choices.”

What’s motivating these unusual actions from pharmaceutical companies?

As noted earlier, these actions are unusual; pharmaceutical companies don’t normally engage in this sort of public-facing transparency while studies are ongoing. There are at least three possible and related reasons we might be seeing such behavior here. 

First, and perhaps most important, vaccine makers and the pharmaceutical industry—really, the entire health-care industry—depend on trust. Patients need to trust that drugs will be safe and effective, or they won’t buy them. The biggest guarantor of that trust is the FDA, which puts its seal of approval on products by allowing them into the marketplace. A high-profile failure here, where a drug company marketed a vaccine that didn’t work or wasn’t safe and the FDA permitted its marketing, would be a colossal blow to trust in the pharmaceutical industry (and a terrible result for society as well). This would ultimately be bad for their bottom lines. And so, while pharmaceutical companies want patients and doctors to trust them, they really want patients to trust the FDA, which provides—or provided—a high baseline level of trust in the drug approval system as a whole.

There are already signs of decreasing trust in the FDA and other government agencies. This mistrust is especially prevalent among minority communities which have been hardest hit by COVID-19—in part because they’ve been the subject of abuses in both research and treatment. Some medical professionals are following suit; the National Medical Association, an organization of Black physicians, has created its own independent task force to vet COVID-19 vaccines. And drug companies have been responding to this minority distrust as well; Moderna announced that it is slowing enrollment in its vaccine trial to ensure that it can enroll sufficient minority patients.

Second, and relatedly, at least some pharmaceutical companies benefit competitively from having a stringent standard for approval. The FDA operates as a gatekeeper to the pharmaceutical market, creating barriers to entry. As Professor Rebecca S. Eisenberg has written, the FDA’s high approval standards force firms to generate high-quality, costly information about safety and efficacy. This costly endeavor is something which large, established players like Pfizer and AstraZeneca can undertake, but is harder for smaller market upstarts (although this argument likely applies with less force to large upstarts like Moderna). For large incumbent firms, maintaining FDA’s high standards isn’t just about keeping trust in the system as a whole—it’s also about keeping their competitive position in the pharmaceutical industry. Even for fast-developing COVID-19 vaccines, there is likely to be competition, and to the extent that high entry barriers are more surmountable by large firms than by others, those large firms have an incentive to keep the barriers high.

Third and finally, the public, and public funders in particular, have been unusually deeply involved in the development of COVID-19 vaccines, whether in terms of basic research, manufacturing assistance, or advance commitments to purchase final products. To be sure, the companies have made enormous investments of private funding and are the ones conducting most of the clinical trials, but the public has been present throughout. Given this robust public involvement, there have been calls and even FOIA requests for more information about the process. To the extent that the relevant information is likely to come out one way or another, proactive disclosure by companies may preempt other avenues of getting the information—and in such a way that the drug companies get the reputational benefit of disclosing on their own. 

How can we encourage the release of information in order to benefit the public?

Developers’ engagement with the public and their efforts at improving transparency in the development process are a good thing. To researchers and the public alike, the particulars about therapeutic and vaccine development have long been hidden in black boxes. Encouraging transparency in their development allows the public to better understand how an industry critical to its health and well-being operates; it also helps researchers better understand important aspects of their work, like decisional inflection points, cost, and pricing. Moreover, in a political climate where trust of public institutions has eroded into dust, developer-side transparency should give us more confidence in the capacity for industry self-governance. Commitments by legacy therapeutic developer CEOs suggests that they understand that they’re stewards of such institutions. But how could such commitments be improved? 

With respect to COVID-19 vaccines, developers could be encouraged to immediately release any clinical trial data once a new phase is completed. Typically, there’s a lag—sometimes a long lag—between the completion and reporting of each phase to the FDA and a “publication summary” of that data for public consumption. This lag exists principally because the FDA treats the particulars of clinical trial data as confidential business information (CBI). Immediate publication of COVID-19 trial data will give everyone a better sense of when a COVID-19 vaccine is likely to arrive and what the ultimate efficacy rate is.

This could be accomplished in several ways. To the extent developer CEOs are, indeed, doing this public road show to shore up public confidence, interviewers could ask them to publicly state that they will release such information earlier than usual. Similarly, scientific journals could make similar commitments about publishing data summaries—namely, that publication won’t happen unless the underlying data has previously been released. (In some sense, this turns the business of publication on its head; in another, it’s no different these days from medRxiv.) In addition, while early data release seems like a wonky issue, it presents an opportunity for public buy-in. Where public confidence in public health policies are low or borderline, trusted actors—whether it is a medical journalist like Sanjay Gupta or a celebrity like Paul Rudd—can use the released evidence to help encourage public participation and uptake.

More broadly, these opportunities for transparency can—and should—extend beyond COVID-19 vaccine development. As noted above, the FDA could do more to enforce existing requirements to disclose clinical trial protocols and data within a year of trial completion. The FDA had, at one point, committed itself to additional reforms regarding its handling of clinical trial data and CBI, although it backtracked soon afterwards. While the FDA has a less than ideal transparency policy on clinical trial data, there are good blueprints out there for making it better within much of the agency’s already existing authority. In addition, some recent regulatory changes to the development process itself “have the potential to improve the efficiency and quality of clinical research by allowing investigators and companies to learn from successes and failures of similar products.” Promoting efficiency in development through transparency is not as radical as it sounds; the European Medicines Agency does far more than the U.S. does regarding transparency, which helps ultimately promote both drug development and public confidence in the process. And if there’s one policy lesson for the U.S. to heed well, it’s to look to our international allies for better strategies to combat the virus.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

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